title: The role of inherited TPMT and COMT genetic variation in cisplatin-induced ototoxicity in children with cancer.
abstract: Ototoxicity is a debilitating side effect of platinating agents with substantial interpatient variability. We sought to evaluate the association of thiopurine S-methyltransferase (TPMT) and catechol O-methyltransferase (COMT) genetic variations with cisplatin-related hearing damage in the context of frontline pediatric cancer treatment protocols. In 213 children from the St. Jude Medulloblastoma-96 and -03 protocols, hearing loss was related to younger age (P = 0.013) and craniospinal irradiation (P = 0.001), but did not differ by TPMT or COMT variants. Results were similar in an independent cohort of 41 children from solid-tumor frontline protocols. Functional hearing loss or hair cell damage was not different in TPMT knockout vs. wild-type mice following cisplatin treatment, and neither TPMT nor COMT variant was associated with cisplatin cytotoxicity in lymphoblastoid cell lines. In conclusion, our results indicated that TPMT or COMT genetic variation was not related to cisplatin ototoxicity in children with cancer and did not influence cisplatin-induced hearing damage in laboratory models.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Yang
authors.forename: J Y S
authors.initials: JY
authors.lastname: Lim
authors.forename: J
authors.initials: J
authors.lastname: Huang
authors.forename: J
authors.initials: J
authors.lastname: Bass
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.forename: J
authors.initials: J
authors.lastname: Fang
authors.forename: E
authors.initials: E
authors.lastname: Stewart
authors.forename: E H
authors.initials: EH
authors.lastname: Harstead
authors.forename: S
authors.initials: S
authors.lastname: E
authors.forename: G W
authors.initials: GW
authors.lastname: Robinson
authors.forename: W E
authors.initials: WE
authors.lastname: Evans
authors.forename: A
authors.initials: A
authors.lastname: Pappo
authors.forename: J
authors.initials: J
authors.lastname: Zuo
authors.forename: M V
authors.initials: MV
authors.lastname: Relling
authors.forename: A
authors.initials: A
authors.lastname: Onar-Thomas
authors.forename: A
authors.initials: A
authors.lastname: Gajjar
authors.forename: C F
authors.initials: CF
authors.lastname: Stewart
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin / Q000633:toxicity*; D061888:Craniospinal Irradiation; D004305:Dose-Response Relationship, Drug; D005260:Female; D034381:Hearing Loss / Q000139:chemically induced*; D006801:Humans; D008297:Male; D008780:Methyltransferases / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout
chemical_list: D000970:Antineoplastic Agents; D008780:Methyltransferases; D002394:Catechol O-Methyltransferase; C022745:thiopurine methyltransferase; D002945:Cisplatin